Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients With Chronic Kidney Disease

Abstract

The endothelium is considered to be the gatekeeper of the vessel wall, maintaining and regulating vascular integrity. In patients with chronic kidney disease, protective endothelial cell functions are impaired due to the proinflammatory, prothrombotic and uremic environment caused by the decline in kidney function, adding to the increase in cardiovascular complications in this vulnerable patient population. In this review, we discuss endothelial cell functioning in healthy conditions and the contribution of endothelial cell dysfunction to cardiovascular disease. Further, we summarize the phenotypic changes of the endothelium in chronic kidney disease patients and the relation of endothelial cell dysfunction to cardiovascular risk in chronic kidney disease. We also review the mechanisms that underlie endothelial changes in chronic kidney disease and consider potential pharmacological interventions that can ameliorate endothelial health.

Keywords: atherosclerosis; cardiovascular diseases; chronic kidney diseases; endothelial cells; vascular stiffness.

Figure 1.

Chronic kidney disease (CKD) prevalence and cardiovascular risk in CKD. A, CKD classification and prevalence. *Compared with young adult level. ^a/bFigure based on data by ^aInker et al and ^bHill et al. B, Percentage of cardiovascular deaths according to CKD stage (age and sex adjusted). Figure based on data by Thompson et al. C, Cardiovascular causes of death in the general population compared with dialysis patients (CKD stage 5D). Figure based on data by Roberts et al. CVD indicates cardiovascular disease; GFR, glomerular filtration rate; and PU, proteinuria.

Figure 2.

Endothelial phenotype in healthy conditions in relation to thrombosis, vasoreactivity and inflammation. Vasodilatory, anti-inflammatory, and antithrombotic characteristics of healthy endothelium. For more information, see text. ADP indicates adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; ATIII, antithrombin III; cAMP, cyclic adenosine monophosphate; CD39, ectonucleoside triphosphate diphosphohydrolase-1; CD73, ecto-5’-nucleotidase; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; EPCR, endothelial protein C receptor; ER, endoplasmic reticulum; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NO, nitric oxide; NRF-2, nuclear factor erythroid 2-related factor 2; PG, proteoglycans; TFPI, tissue factor pathway inhibitor; and ZO, zonula occludens.

Figure 3.

Endothelial phenotype in chronic kidney disease (CKD) conditions in relation to thrombosis. Endothelial phenotype in CKD conditions in terms of thrombosis. For more information, see text. cLDL indicates carbamylated low-density lipoprotein; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; LOX-1, lectin-type oxidized low-density lipoprotein receptor 1; NO, nitric oxide; oxLDL, oxidized low-density lipoprotein; PAI-1, plasminogen activator inhibitor-1; TF, tissue factor; and vWF, von Willebrand factor.

Figure 4.

Endothelial phenotype in chronic kidney disease (CKD) conditions in relation to inflammation and atherosclerosis. Endothelial phenotype in CKD conditions in terms of proinflammatory and proatherosclerotic characteristics. For more information, see text. ATF indicates activating transcription factor; cLDL, carbamylated low-density lipoprotein; CREB, cyclic adenosine monophosphate response element-binding protein; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; E-selectin, endothelial-leukocyte adhesion molecule 1; HCO₃⁻, bicarbonate; H₂O₂, hydrogen peroxide; ICAM-1, intercellular adhesion molecule 1; LOX-1, lectin-type oxidized low-density lipoprotein receptor 1; NADPH, nicotinamide adenine dinucleotide phosphate; NET, neutrophil extracellular trap; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; O₂, oxygen; O₂^*−, superoxide; oxHDL, oxidized high-density lipoprotein; oxLDL, oxidized low-density lipoprotein; P-selectin, granule membrane protein 140; ROS, reactive oxygen species; SDMA, symmetric dimethylarginine; TLR2, toll-like receptor 2; VCAM-1, vascular cell adhesion molecule 1; and ZO, zonula occludens.

Figure 5.

Endothelial phenotype in chronic kidney disease (CKD) conditions in relation to vasoreactivity. Endothelial phenotype in CKD conditions in terms of vasodilation/vasoconstriction. For more information, see text. eNOS indicates endothelial nitric oxide synthase; ER, endoplasmic reticulum; HCO₃⁻, bicarbonate; HDL, high-density lipoprotein; H₂O₂, hydrogen peroxide; LOX-1, lectin-type oxidized low-density lipoprotein receptor 1; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOX, NADPH oxidase; O₂, oxygen; O₂^*−, superoxide; SDMA, symmetric dimethylarginine; TLR2, toll-like receptor 2; and TNFɑ, tumor necrosis factor ɑ.

Figure 6.

Overview of endothelium-dependent vasoreactivity analysis in patients. For a more in-depth discussion of these methods, we refer to 2 excellent reviews.^, CBF indicates coronary blood flow; FMD, flow-mediated dilation; and PAT, peripheral arterial tonometry.